PROJECT 3 ? BIOMEDICAL PROJECT 1 (BP1) - SUMMARY With partnering Native American communities, the UNM Metals Exposure and Toxicity Assessment on Tribal Lands in the Southwest (UNM METALS) team has obtained evidence for community level exposures and health risks associated with more than 1100 abandoned uranium mine (AUM) waste sites on their tribal lands. This project will address underlying mechanisms to account for immune dysregulation, including early molecular markers of autoimmunity, associated with proximity to AUM and uranium and mixed metal exposure. Biomonitoring results confirm that community members are exposed to uranium and other metals beyond national norms. Our published and preliminary work shows that certain metals interact with key cellular targets to disrupt zinc-dependent protein function. We will test the hypothesis that metals disrupt multiple classes of zinc binding proteins known to regulate immune responses, and that supplemental zinc will mitigate immunotoxicity resulting from metal exposures. In Aim 1 aim we will investigate whether serum zinc sufficiency modifies immune dysregulation in individuals exposed to environmental metals by performing a cross-sectional analysis of archived population samples for associations between markers of immune function with metal and zinc levels present in blood and urine samples. Aim 2 will test the immunotoxic effects and underlying mechanisms of U, As and environmentally relevant metal mixtures defined by the Environmental Projects, and whether the immunotoxic effects are reduced by supplemental zinc in cell and mouse models. Aim 3 will test whether dietary zinc supplementation will decrease biomarkers of immune dysregulation in exposed populations in partnership with exposed communities. The work is innovative by combining exposure information and biomonitoring data from exposed populations with mechanistic studies in experimental models. To date, there are no significant, community-based health studies describing both exposure and immunologic outcome measures in these impacted Tribal communities. We propose a novel hypothesis that metals exposures disrupt multiple classes of Zn binding proteins critical for immune function leading to immune dysregulation and that supplemental Zn will mitigate metal toxicity. This study represents the first human intervention based on zinc supplementation to ameliorate the adverse effects of mixed metal exposures. To achieve the research goals, BP1 is well integrated with the Environmental Projects to inform distinct metals exposures, BP2 to share mechanistic data and model systems, the Community Engagement and Research Translation Cores for community input and reporting results back to the communities, and the Biostatistics and Data Management Core for research support. The outcomes from these studies will be significant by testing metals and metals mixtures of concern to communities to elucidate impact on and mechanisms of immune dysregulation as detected in exposed populations, and test the feasibility of a mechanism-based intervention to alleviate the adverse effects of metals exposures.